Abstract Background Heterogeneity in the biology of colorectal cancer (CRC) is associated with variable responses to standard chemotherapy. We aimed to identify DNA hypermethylated genes as predictive biomarkers for irinotecan treatment of patients with metastatic CRC. Material and Methods The presence of DNA methylation for a selected panel of 22 genes was assessed by methylation specific PCR (MSP) on primary tumors of 185 patients with metastatic CRC treated with first-line capecitabine (CAP, n=90) or a combination of capecitabine and irinotecan (CAPIRI, n=95) in the phase III CAIRO trial. Methylation status of each gene was correlated to progression free survival (PFS) by treatment regimen. Genes for which methylation status associated with response to irinotecan, were validated in 166 patients treated with first-line CAP (n=78) or CAPIRI (n=88). Results Decoy Receptor 1 (DCR1) was identified as a novel hypermethylated gene in CRC. In CAPIRI treated patients, DCR1 methylation was correlated to a shorter PFS compared to patients with unmethylated DCR1 (hazard ratio HR=0.4 (95%CI =0.3-0.7), p = 0.0009). In patients with methylated DCR1 PFS did not improve with CAPIRI treatment, compared to treatment with CAP (discovery set: HR=0.8 (95%CI=0.5-1.3, p=0.4); validation set: HR=1.1 (95%CI 0.7-1.7, p=0.6)), in contrast to patients with unmethylated DCR1 (discovery set: HR=2.5 (95%CI 1.7-3.3, p=0.00004); validation set: HR=1.7 (95%CI 1.1-2.0, p=0.004)). Conclusion CRC patients with methylated DCR1 did not benefit from adding irinotecan to capecitabine therapy, indicating that DCR1 methylation status may guide selecting metastatic CRC patients for irinotecan-based therapy. Citation Format: Linda JW Bosch, Geert Trooskens, Petur Snaebjornsson, Josien C. Haan, Lorraine Pelosof, Miriam Koopman, Jolien Tol, Joost Louwagie, Luc Dehaspe, Bauke Ylstra, Henk Verheul, Manon van Engeland, Iris D. Nagtegaal, James G. Herman, Cornelis JA Punt, Wim van Criekinge, Beatriz Carvalho, Gerrit A. Meijer. Promoter CpG island hypermethylation of Decoy Receptor 1 (DCR1) is associated with poor response to irinotecan in colorectal cancer. abstract. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1155. doi:10.1158/1538-7445.AM2013-1155